Chromomycin A<sub>2</sub>potently inhibits glucose-stimulated insulin secretion from pancreatic β cells

Kalwat, Michael A.; Hwang, In Hyun; Macho, Jocelyn; Grzemska, Magdalena; Yang, Jonathan Z.; McGlynn, Kathleen; MacMillan, John B.; Cobb, Melanie H.

doi:10.1101/337113

Cited by 1 publication

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“…We have recently observed that an important epigenetic reader protein TCF19, interacts with H3K4Me3 via its plant homeodomain (PHD) finger and recruits chromatin remodeling complex NuRD to repress gluconeogenic gene expression 4 . TCF19 is also found to be important in glucose‐stimulated insulin secretion (GSIS) 5 and causes repression of de novo glucose production in HepG2 cells 4 . TCF19 was initially discovered as a growth‐regulated cDNA 6 and was later shown to be involved in maintaining a fine balance between cell proliferation and apoptosis in mouse pancreatic β‐cells 7 .…”

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confidence: 99%

TCF19 and p53 regulate transcription of TIGAR and SCO2 in HCC for mitochondrial energy metabolism and stress adaptation

et al. 2021

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Alteration in glucose homeostasis during cancer metabolism is an important phenomenon. Though several important transcription factors have been well studied in the context of the regulation of metabolic gene expression, the role of epigenetic readers in this regard remains still elusive. Epigenetic reader protein transcription factor 19 (TCF19) has been recently identified as a novel glucose and insulin‐responsive factor that modulates histone posttranslational modifications to regulate glucose homeostasis in hepatocytes. Here we report that TCF19 interacts with a non‐histone, well‐known tumor suppressor protein 53 (p53) and co‐regulates a wide array of metabolic genes. Among these, the p53‐responsive carbohydrate metabolic genes Tp53‐induced glycolysis and apoptosis regulator (TIGAR) and Cytochrome C Oxidase assembly protein 2 (SCO2), which are the key regulators of glycolysis and oxidative phosphorylation respectively, are under direct regulation of TCF19. Remarkably, TCF19 can form different transcription activation/repression complexes which show substantial overlap with that of p53, depending on glucose‐mediated variant stress situations as obtained from IP/MS studies. Interestingly, we observed that TCF19/p53 complexes either have CBP or HDAC1 to epigenetically program the expression of TIGAR and SCO2 genes depending on short‐term high glucose or prolonged high glucose conditions. TCF19 or p53 knockdown significantly altered the cellular lactate production and led to increased extracellular acidification rate. Similarly, OCR and cellular ATP production were reduced and mitochondrial membrane potential was compromised upon depletion of TCF19 or p53. Subsequently, through RNA‐Seq analysis from patients with hepatocellular carcinoma, we observed that TCF19/p53‐mediated metabolic regulation is fundamental for sustenance of cancer cells. Together the study proposes that TCF19/p53 complexes can regulate metabolic gene expression programs responsible for mitochondrial energy homeostasis and stress adaptation.

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Section: Introductionmentioning

confidence: 99%

TCF19 and p53 regulate transcription of TIGAR and SCO2 in HCC for mitochondrial energy metabolism and stress adaptation

et al. 2021

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Chromomycin A₂potently inhibits glucose-stimulated insulin secretion from pancreatic β cells

Abstract: words)Enhancers or inhibitors of insulin secretion could become therapeutics as well as lead to the identification of requisite -cell regulatory pathways and increase our understanding

Cited by 1 publication

References 57 publications

TCF19 and p53 regulate transcription of TIGAR and SCO2 in HCC for mitochondrial energy metabolism and stress adaptation

TCF19 and p53 regulate transcription of TIGAR and SCO2 in HCC for mitochondrial energy metabolism and stress adaptation

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Chromomycin A2potently inhibits glucose-stimulated insulin secretion from pancreatic β cells

Abstract: words)Enhancers or inhibitors of insulin secretion could become therapeutics as well as lead to the identification of requisite -cell regulatory pathways and increase our understanding

Cited by 1 publication

References 57 publications

TCF19 and p53 regulate transcription of TIGAR and SCO2 in HCC for mitochondrial energy metabolism and stress adaptation

TCF19 and p53 regulate transcription of TIGAR and SCO2 in HCC for mitochondrial energy metabolism and stress adaptation

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Chromomycin A₂potently inhibits glucose-stimulated insulin secretion from pancreatic β cells